We have previously demonstrated that left ventricular (LV)ejection fraction -(EF) at rest and during exercise stratifies patients with mildly symptomatic coronary artery disease (CAD) according to the risk of multivessel CAD and of death during the course of medical therapy. To determine if subsequent changes in EF with time signify important changes in coronary anatomy, we studied 90 mildly symptomatic pts with two coronary angiograms spanning 2-12 yr (mean 5 yr) of medical therapy and with serial radionuclide angiograms at rest and during exercise every 1-2 yrs, after withdrawal of all anti-ischemic drugs. We observed that progression of CAD by coronary arteriography was rare in the absence of changes in LV function at rest or exercise. However, progressive CAD developed in the majority of patients manifesting either a reduction in resting EF or a deterioration in the EF response to exercise, even in the absence of progression of anginal symptoms. In these latter patients, there was also a high likelihood of the development of new total coronary artery obstructions or new left main stenoses. These data allowed us to address another issue that has been raised in mildly symptomatic patients with CAD and inducible ischemia. We found that it was rare for LV function at rest to deteriorate with time in the absence of a new 100% coronary artery obstruction, even in patients with repeated evidence of recurrent episodes of myocardial ischemia. Thus, recurrent myocardial ischemia, in and of itself, does not appear to predispose to the development of LV dysfunction in the absence of anatomic progression of CAD in humans.